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Synaptic dysfunction is increasingly recognized as a core feature of psychiatric disorders, yet fluid biomarkers that reflect such changes in vivo are lacking. Here, we applied targeted mass spectrometry to quantify low-abundant synaptic proteins in cerebrospinal fluid from 672 individuals with anorexia nervosa, attention-deficit/hyperactivity disorder (ADHD), bipolar disorder (BD), schizophrenia spectrum disorders (SCZ + ), and healthy controls. Synaptic protein levels were markedly reduced in SCZ + , with intermediate reductions in BD and ADHD. Using a data-driven approach to model transdiagnostic contrasts-psychotic experience, cognitive and functional impairment-a shared two-biomarker signature emerged: elevated LAMP1, a phagolysosomal marker, and reduced NPTX2, a synaptic activity marker which inhibits complement-dependent synapse elimination. Combining this ratio with polygenic scores improved diagnostic classification. Key findings were extended to an independent cohort at first-episode psychosis. These results support synaptic pathology as a measurable and transdiagnostic feature across several psychiatric disorders and highlight the potential of integrating fluid and genetic biomarkers.